Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma
Michael A. Gillette(Broad Institute), Shankha Satpathy(Broad Institute), Song Cao(Washington University in St. Louis), Saravana M. Dhanasekaran(University of Michigan), Suhas Vasaikar(The University of Texas MD Anderson Cancer Center), Karsten Krug(Broad Institute), Francesca Petralia(Icahn School of Medicine at Mount Sinai), Yize Li(Washington University in St. Louis), Wen-Wei Liang(Washington University in St. Louis), Boris Reva(Icahn School of Medicine at Mount Sinai), Azra Krek(Icahn School of Medicine at Mount Sinai), Jiayi Ji(Tisch Hospital), Xiaoyu Song(Tisch Hospital), Wenke Liu(Institute for Systems Biology), Runyu Hong(Institute for Systems Biology), Lijun Yao(Washington University in St. Louis), Lili M. Blumenberg(Institute for Systems Biology), Sara R. Savage(Baylor College of Medicine), Michael C. Wendl(Washington University in St. Louis), Bo Wen(Baylor College of Medicine), Kai Li(Baylor College of Medicine), Lauren C. Tang(Broad Institute), Melanie A. MacMullan(Broad Institute), Shayan C. Avanessian(Broad Institute), M. Harry Kane(Broad Institute), Chelsea J. Newton(Van Andel Institute), MacIntosh Cornwell(Institute for Systems Biology), Ramani Kothadia(Broad Institute), Weiping Ma(Icahn School of Medicine at Mount Sinai), Seungyeul Yoo(Icahn School of Medicine at Mount Sinai), Rahul Mannan(University of Michigan), Pankaj Vats(University of Michigan), Chandan Kumar‐Sinha(University of Michigan), Emily Kawaler(Institute for Systems Biology), Tatiana Omelchenko(Memorial Sloan Kettering Cancer Center), Antonio Colaprico(University of Miami), Yifat Geffen(Broad Institute), Yosef E. Maruvka(Broad Institute), Felipe da Veiga Leprevost(University of Michigan), Maciej Wiznerowicz(Poznan University of Medical Sciences), Zeynep H. Gümüş(Icahn School of Medicine at Mount Sinai), Rajwanth Veluswamy(Icahn School of Medicine at Mount Sinai), Galen Hostetter(Van Andel Institute), David I. Heiman(Broad Institute), Matthew A. Wyczalkowski(Washington University in St. Louis), Tara Hiltke(National Cancer Institute), Mehdi Mesri(National Cancer Institute), Christopher R. Kinsinger(National Cancer Institute), Emily S. Boja(National Cancer Institute), Gilbert S. Omenn(University of Michigan), Arul M. Chinnaiyan(University of Michigan), Henry Rodriguez(National Cancer Institute), Qing Kay Li(Johns Hopkins University), Scott D. Jewell(Van Andel Institute), Mathangi Thiagarajan(Leidos (United States)), Gad Getz(Broad Institute), Bing Zhang(Baylor College of Medicine), David Fenyö(Institute for Systems Biology), Kelly V. Ruggles(Institute for Systems Biology), Marcin Cieślik(University of Michigan), Ana I. Robles(National Cancer Institute), Karl R. Clauser(Broad Institute), Ramaswamy Govindan(Washington University in St. Louis), Pei Wang(Icahn School of Medicine at Mount Sinai), Alexey I. Nesvizhskii(University of Michigan), Li Ding(Washington University in St. Louis), D.R. Mani(Broad Institute), Steven A. Carr(Broad Institute), Alex Webster(University of Michigan), Alicia Francis(Fusion (United States)), Alyssa Charamut(Fusion (United States)), Amanda G. Paulovich(Fusion (United States)), Amy M. Perou(Fusion (United States)), Andrew K. Godwin(Fusion (United States)), Andrii Karnuta(Fusion (United States)), Annette Marrero-Oliveras(Fusion (United States)), Barbara Hindenach(Fusion (United States)), Barbara L. Pruetz(Fusion (United States)), Bartosz Kubisa(Fusion (United States)), Brian Druker(Fusion (United States)), Chet Birger(Fusion (United States)), Corbin D. Jones(Fusion (United States)), Dana R. Valley(Fusion (United States)), Daniel C. Rohrer(Fusion (United States)), Daniel Cui Zhou(Fusion (United States)), Daniel W. Chan(University of Michigan), David Chesla(Institute for Systems Biology), David Clark(Fusion (United States)), Dmitry Rykunov(Fusion (United States)), Donghui Tan(Broad Institute), Elena V. Ponomareva(Fusion (United States)), Elizabeth R. Duffy(Fusion (United States)), Eric Burks(Fusion (United States)), Eric E. Schadt(Fusion (United States)), Erik J. Bergstrom(Fusion (United States)), Eugene Fedorov(Fusion (United States)), Ewa P. Malc(Fusion (United States)), George D. Wilson(Fusion (United States)), Haiquan Chen(Memorial Sloan Kettering Cancer Center), Halina Krzystek(Fusion (United States)), Hongwei Liu(Institute for Systems Biology), Houston Culpepper(Fusion (United States)), Hua Sun(Fusion (United States)), Hui Zhang(Baylor College of Medicine), Jacob Day(Fusion (United States)), James Suh(The University of Texas MD Anderson Cancer Center), Jeffrey R. Whiteaker(Fusion (United States)), Jennifer Eschbacher(Fusion (United States)), John P. McGee(Fusion (United States)), Karen A. Ketchum(Fusion (United States)), Karin Rodland(Fusion (United States)), Karna Robinson(Fusion (United States)), Katherine A. Hoadley(Fusion (United States)), Kei Suzuki(Fusion (United States)), Ki Sung Um(Fusion (United States)), Kim Elburn(Fusion (United States)), Liang-Bo Wang(Icahn School of Medicine at Mount Sinai), Lijun Chen(Memorial Sloan Kettering Cancer Center), Linda I. Hannick(Fusion (United States)), Liqun Qi(Johns Hopkins University), Lori J. Sokoll(Fusion (United States)), Małgorzata Wojtyś, Marcin J. Domagalski(Fusion (United States)), Marina A. Gritsenko(Fusion (United States)), Mary Beth Beasley(Fusion (United States)), Matthew Monroe(Fusion (United States)), Matthew J. Ellis(Fusion (United States)), Maureen A. Dyer(Fusion (United States)), Meghan C. Burke(Fusion (United States)), Melissa Borucki(Fusion (United States)), Menghong Sun(Fusion (United States)), Michael H. A. Roehrl(Fusion (United States)), Michael J. Birrer(Fusion (United States)), Michael S. Noble(Washington University in St. Louis), Michael Schnaubelt(Washington University in St. Louis), Michael W. Vernon(Washington University in St. Louis), Michelle Chaikin(Fusion (United States)), Mikhail Krotevich(Fusion (United States)), Munziba Khan(Fusion (United States)), Myvizhi Esai Selvan(Fusion (United States)), Nancy Roche(Fusion (United States)), Nathan Edwards(Fusion (United States)), Negin Vatanian(Fusion (United States)), Olga Potapova(Fusion (United States)), Pamela Grady(Fusion (United States)), Peter B. McGarvey(Fusion (United States)), Piotr A. Mieczkowski(Fusion (United States)), Pushpa Hariharan(Fusion (United States)), Rashna Madan(Fusion (United States)), Ratna R. Thangudu(Fusion (United States)), Richard Smith(Fusion (United States)), Robert Welsh(Fusion (United States)), Robert Zelt(Fusion (United States)), Rohit Mehra(Fusion (United States)), Ronald Matteotti(Fusion (United States)), Sailaja Mareedu(Fusion (United States)), Samuel Payne(Fusion (United States)), Sandra Cottingham(Fusion (United States)), Sanford P. Markey(Fusion (United States)), Seema Chugh(Fusion (United States)), Shaleigh Smith(Fusion (United States)), Shirley Tsang(Fusion (United States)), Shuang Cai(Fusion (United States)), Simina M. Boca(Fusion (United States)), Sonya Carter(Fusion (United States)), Stacey Gabriel(Fusion (United States)), Stephanie Young, Stephen E. Stein, Sunita Shankar, Tanya Krubit, Tao Liu(Institute for Systems Biology), Tara Skelly(National Cancer Institute), Thomas Bauer, Uma Velvulou(University of Michigan), Umut Özbek, Vladislav Petyuk, Volodymyr Sovenko, William Bocik, William W. Maggio, Xi Chen(Memorial Sloan Kettering Cancer Center), Yan Shi(University of Michigan), Yige Wu, Yingwei Hu(University of Michigan), Yuxing Liao, Zhen Zhang(Baylor College of Medicine), Zhiao Shi(Fusion (United States))
Cited by 814Open Access
Abstract
To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.
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